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Effects on fertility

Description of key information

RAC/35/2015/09 (Amendment to the RAC note “Application for Authorisation: Establishing a reference dose-response relationship for carcinogenicity of hexavalent chromium” to include the intrinsic property “Toxic to reproduction” of the Cr(VI) compounds (RAC/27/2013/06 Rev.1) agreed on 4 December 2013 at RAC- 27) gives a comprehensive overview about available study data on reprotoxic effects from Cr(VI) compounds. In this document it is resumed:

“All the available experimental studies evaluating the potential reproductive effects of hexavalent chromium used the water-soluble compounds potassium dichromate, sodium dichromate or chromium trioxide (chromic acid) and the oral exposure route. Standard reproductive toxicity studies have been conducted in several species - monkeys, rats, mice and rabbits. In addition, several studies have specifically evaluated the potential effects of pre- gestational, gestational, or lactational exposure on foetal development in rats and mice.

Animals were exposed through the diet, drinking water or by gavage. In general, studies that evaluated developmental effects of hexavalent chromium were conducted at higher exposure levels than those that evaluated fertility effects. Unfortunately, a substantial proportion of the available studies were relatively old, not very well reported and not in line with current standards.

Collectively, the available studies provide evidence that oral exposure of laboratory animals to hexavalent chromium compounds can produce adverse reproductive effects, including: histopathological changes to reproductive organs in males and females; alterations in sperm, including decreased count, decreased motility, and abnormal morphology; decreased plasma testosterone levels; increased oestrous cycle length; changes in mating behaviour and decreased fertility in males; and adverse reproductive outcomes, including decreased numbers of live foetuses and implantations, and increased numbers of resorptions and pre- and post- implantation losses.

Developmental effects observed included: decreased foetal weight and length; external and skeletal abnormalities; and delayed sexual maturation in female offspring.

A key step in the analysis would normally be the identification of an appropriate NOAEL from a reliable study. Unfortunately, from the overall data available, such a reliable NOAEL value is not apparent; therefor an approach based on reliable LOAEL values has been used.”

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
5.2 mg/kg bw/day
Additional information

The following study was selected in RAC/35/2105/09 for the derivation of a DNEL valus for fertility effects:

For fertility effects, including effects on reproductive organs, after considering all the most adequate available studies, the Li et al (2001) study was selected as it provides the most sensitive and sufficiently reliable toxicological starting point (oral LOAEL of 5.2 mg Cr(VI)/kg bw/d) for effects on the testes in rats treated for 6 days.

The only lower NOAEL and LOAEL values (around 1-2 mg Cr(VI)/kg bw/d) for effects on male reproductive organs were identified in monkey studies. However, due to the very low sample size employed, no reliable conclusions could be drawn from these studies. Hence the chosen starting point is the most conservative of the more reliable values available.

Effects on developmental toxicity

Description of key information

RAC/35/2015/09 (Amendment to the RAC note “Application for Authorisation: Establishing a reference dose-response relationship for carcinogenicity of hexavalent chromium” to include the intrinsic property “Toxic to reproduction” of the Cr(VI) compounds (RAC/27/2013/06 Rev.1) agreed on 4 December 2013 at RAC- 27) gives a comprehensive overview about available study data on reprotoxic effects from Cr(VI) compounds. In this document it is resumed:

“All the available experimental studies evaluating the potential reproductive effects of hexavalent chromium used the water-soluble compounds potassium dichromate, sodium dichromate or chromium trioxide (chromic acid) and the oral exposure route. Standard reproductive toxicity studies have been conducted in several species - monkeys, rats, mice and rabbits. In addition, several studies have specifically evaluated the potential effects of pre- gestational, gestational, or lactational exposure on foetal development in rats and mice.

Animals were exposed through the diet, drinking water or by gavage. In general, studies that evaluated developmental effects of hexavalent chromium were conducted at higher exposure levels than those that evaluated fertility effects. Unfortunately, a substantial proportion of the available studies were relatively old, not very well reported and not in line with current standards.

Collectively, the available studies provide evidence that oral exposure of laboratory animals to hexavalent chromium compounds can produce adverse reproductive effects, including: histopathological changes to reproductive organs in males and females; alterations in sperm, including decreased count, decreased motility, and abnormal morphology; decreased plasma testosterone levels; increased oestrous cycle length; changes in mating behaviour and decreased fertility in males; and adverse reproductive outcomes, including decreased numbers of live foetuses and implantations, and increased numbers of resorptions and pre- and post- implantation losses.

Developmental effects observed included: decreased foetal weight and length; external and skeletal abnormalities; and delayed sexual maturation in female offspring.

A key step in the analysis would normally be the identification of an appropriate NOAEL from a reliable study. Unfortunately, from the overall data available, such a reliable NOAEL value is not apparent; therefor an approach based on reliable LOAEL values has been used.”

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
7.9 mg/kg bw/day
Additional information

For developmental effects, after considering all the most adequate of the available studies, the Elsaieed and Nada (2002) study was selected as it provides the most sensitive and sufficiently reliable toxicological starting point (oral LOAEL of 7.9 mg Cr(VI)/kg bw/d) for a number of foetal effects (in the absence of significant maternal toxicity) in rats during gestation.

There are a number of uncertainties on how the value of 7.9 mg Cr(VI)/kg bw/d was derived. However, NOAEL and LOAEL values from other developmental toxicity studies are higher, which indicates that the proposed starting point is the most conservative.

Justification for classification or non-classification

Dichromium tris(chromate) is not classified as toxic to reproduction according to Regulation (EC) No 1272/2008. Other Cr (VI) water-soluble salts such as potassium dichromate and sodium dichromate are classified as Category 1B reproductive toxins according to Regulation (EC) No 1272/2008. It is proposed, based on the body of data indicating that Cr (VI) compounds might be reproductive toxicants, that dichromium tris(chromate) is classified as 'Toxic to Reproduction Category 2', according to Regulation (EC) No 1272/2008.